ABSTRACT A fundamental outstanding question in cellular development remains how epigenetic mechanisms of gene regulation are coordinated during development and their role in disease. Genome structure and topology, local chromatin landscape, and non-coding RNAs all contribute to epigenetic transcriptional regulation. Moreover, alterations in these elements or factors can perturb gene expression and promote disease pathogenesis, as shown for B cell lymphoma (Koues et al, Immunity 2015). While the general principles of these mechanisms are widely accepted, the specific identity and interplay of these elements at individual gene loci is largely unknown. Therefore, the proposed studies will define regulatory interactions at a single locus containing two genes that are essential for normal immune function and, when deregulated, promote auto-immunity or cancer. FAIM3 (TOSO, FCMR) is an IgM receptor expressed in innate and adaptive immune cells, and PIGR encodes the IgA receptor and secreted IgA in mucosal epithelial cells. Importantly, preliminary studies show that regulatory elements and a lncRNA in this locus are deregulated in B cell lymphomas and leukemia. By elucidating the regulatory mechanisms that control expression of these genes in a cell-specific manner, the key elements necessary for lineage specificity and how these regulatory mechanisms are corrupted in lymphoid cancers will be revealed. Aim 1 will define the genomic organization and 3-dimensional structure of the locus. In addition, Aim 1 studies will determine the contribution of regulatory elements to maintaining this structure and transcriptional control of FAIM3, PIGR, and neighboring genes. Aim 2 will elucidate the transcription factors that serve as key regulators of FAIM3 and PIGR and determine how genetic polymorphisms and mutations alter this regulation through perturbation of transcription factor binding. Aim 3 will characterize a novel long non-coding RNA, confirming its full sequence, verifying its exonic structure, and determining whether it contributes to the transcriptional control of FAIM3 or PIGR. Upon completion of these studies, the regulatory elements and mechanisms that control the cell-specific expression of FAIM3 and PIGR will be defined, as will how these genes are altered in lymphoid cancer. The impact of these studies will reach beyond a single gene locus, by providing a window into the intricate interplay of epigenetic and genetic mechanisms of gene regulation and deregulation in normal development and cancer.